E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic fungal infection |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of disease caused by Candida albicans |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042941 |
E.1.2 | Term | Systemic fungal infection NOS |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the pharmacokinetics of voriconazole following intravenous to oral switch in children aged 2 to less than (<) 12 years.
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of multiple dose administration of voriconazole in children requiring treatment for the prevention of systemic fungal infection.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects (both male and female) from 2 to less than (<)12 years of age who require treatment for the prevention of systemic fungal infection, and who can tolerate being switched to oral therapy between Days 8 and 12.
2. Subjects who are expected to develop neutropenia (absolute neutrophil count [ANC < 500/microliter [µl]) lasting more than 10 days following chemotherapy for one of the following conditions:
a. Leukemia, including ALL, AML and relapsed leukemia
b. Lymphoma, including relapsed lymphoma
c. Aplastic anemia
d. As the preparative regimen for bone marrow or stem cell transplantation
3. Subjects who are anticipated to live for more than 3 months |
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E.4 | Principal exclusion criteria |
1. Subjects who are receiving and cannot discontinue the following drugs at least 24 hours prior to study start, or, if they need to commence any of the following during the study:
a. Terfenadine, pimozide, quinidine, astemizole and cisapride (due to the possibility of QTc prolongation)
b. Omeprazole (an inhibitor of cytochrome P450 2C19 [CYP2C19] which is known to increase plasma voriconazole levels)
c. Ergot alkaloids
2. Subjects who have received the following drugs within 14 days
prior to study entry:
Rifampicin, rifampin, rifabutin, carbamazepine, phenytoin, nevirapine and long acting barbiturates as these are inducers of hepatic enzymes and may result in undetectable levels of voriconazole.
a. Sirolimus as voriconazole is known to increase significantly sirolimus blood levels.
3. Subjects with any clinically significant abnormality following review of screening laboratory data other than that associated with their underlying disease.
4. Liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin) > 5 * upper limit of normal [ULN].
5. In subjects with clinically relevant hypokalemia potassium needs to be corrected before initiation of study treatment.
6. Subjects who are taking, or are likely to receive, any investigational drug other than chemotherapy, antiretroviral agents, and drugs used for the treatments of AIDS defining opportunistic infections, all of which are allowed.
7. Subjects with a history of hypersensitivity to or severe intolerance of azole antifungal agents.
8. Subjects who have already been entered into this protocol Subjects with moderate and severe renal impairment (i.e., calculated creatinine clearance <30 milliliter per minute (ml/min). Creatinine clearance will be calculated using the equation:
Creatinine Clearance (ml/min) = 0.55*height (centimeter [cm])/serum creatinine (milligram per deciliter [mg/dL])
9. Subjects who have prior or current evidence of cardiac
arrhythmia.
10. Females of child-bearing potential. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Area Under the Curve from Time Zero to end of dosing interval (AUCtau).
2. Maximum Observed Plasma Concentration (Cmax).
3. Time to Reach Maximum Observed Plasma Concentration (Tmax).
4. Bioavailability (F) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. 2min pre-infusion end and 4, 6, 8 and 12hour (h) post-infusion start on day 4 and day 12.
2. 2min pre-infusion end and 4, 6, 8 and 12h post-infusion start on day 4 and day 12.
3. 2min pre-infusion end and 4, 6, 8 and 12h post-infusion start on day 4 and day 12.
4. 2min pre-infusion end and 4, 6, 8 and 12h post-infusion start on day 4 anad day 12. |
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E.5.2 | Secondary end point(s) |
Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 20 |